Dopamine synthesis capacity and tau pathology differentially modulate rest-to-task functional network dynamics

Optimal cognition relies on large-scale functional brain networks which balance segregation at rest with selective integration during task performance. In aging, these network dynamics are altered. We examined two prominent features of brain aging: dysregulated dopamine function and Alzheimer's disease (AD)-related pathology to examine impacts on brain network dynamics. Young adults and cognitively unimpaired older adults completed resting-state and task-based fMRI and PET imaging of dopamine synthesis capacity ([ 18 F]fluoro-m-L-tyrosine). Older adults were classified as β-amyloid negative/positive using [ 11 C]Pittsburgh Compound-B PET(PiB- or PiB+) and underwent tau-PET scanning ([ 18 F]flortaucipir). Greater rest-to-task network stability and task-related network segregation were associated with better subsequent memory. Compared to young adults, PiB+ older adults showed reduced network stability and both PiB+ and PiB- older adults showed reduced segregation during rest. Higher ventral striatal dopamine synthesis capacity was associated with greater stability within associative networks in young adults, but this relationship was attenuated in older adults and absent in PiB+ participants. In PiB+ older adults, higher tau burden was associated with a task-induced collapse of network segregation across large-scale networks. These findings reveal dissociable influences of dopamine and tau on rest-to-task network organization, highlighting the value of integrating neuromodulatory and pathological markers in aging research.